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BackgroundRavulizumab is a long-acting C5 complement inhibitor that provides sustained suppression of the complement pathway. It is currently approved by the US Food and Drug Administration (FDA) for the treatment of generalized myasthenia gravis, paroxysmal nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome. With its increasing clinical use, concerns regarding Ravulizumab-associated adverse drug reactions have grown.MethodsThis study utilized a dataset extracted from the Adverse Event Reporting System (FAERS) database, comprising adverse event reports from the fourth quarter of 2018 to the second quarter of 2025. Four distinct disproportionality analysis methods—the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN)—were applied. Additionally, the time-to-onset profile of adverse events was assessed using the Weibull distribution model.ResultsA total of 9,090 adverse event reports associated with ravulizumab were included in this analysis. Commonly reported adverse events included fatigue, asthenia, headache, malaise, dyspnea, back pain, feeling abnormal, and diplopia. Furthermore, potential adverse events not listed on the drug label were identified, such as anemia, dysphagia, urinary tract infection, and somnolence.ConclusionThis investigation identified several adverse events associated with ravulizumab and revealed potential adverse reaction signals that were not previously recognized. Healthcare providers may consider these safety signals to more comprehensively assess potential risks in patients during clinical practice.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270–360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90–18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease. Eculizumab has revolutionized the treatment of PNH and aHUS although has been less successful in C3G. With the next generation of complement therapeutic in late stage development, these archetypal complement diseases will provide the initial targets.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients’ quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder which is caused by mutations in phosphatidylinositol glycan class A leading to hemolysis of red blood cells via complement inhibition. The first treatment for PNH, eculizumab, was FDA approved in 2007. Since then, many new treatment options for PNH have arisen. This critical review will examine all medications available for PNH on the US market, highlight several major medications in development, and discuss the risks and treatment considerations associated with each option. It is not intended to address PNH clonal dynamics, disease presentation, or discussions on when to initiate treatment. Plain language summary Current treatment options for paroxysmal nocturnal hematuria and prices Treatment options for paroxysmal nocturnal hematuria have changed significantly since 2007, when the first medication for this disease was approved in the United States. This review begins by explaining the biochemical pathways that explain the pathophysiology of paroxysmal nocturnal hemoglobinuria. Then, various effects of the disease and treatments including breakthrogh intravascular hemolysis and extravascular hemolysis are explained. Finally, each treatment option for paroxysmal nocturnal hemoglobinuria is discussed and compared in terms of effectiveness, price, and how often the patient needs to take the medication.

Background Paroxysmal nocturnal haemoglobinuria (PNH) is characterised by haemolytic anaemia, bone marrow failure and thrombosis. The single‐arm phase 3 APPOINT‐PNH trial (NCT04820530) investigating iptacopan monotherapy in complement inhibitor‐naive patients demonstrated significant haemoglobin concentration improvements. Methods We used target trial emulation to retrospectively predict outcomes if APPOINT‐PNH trial patients had received C5 inhibitors instead of iptacopan. Estimates were derived from the real‐world APPEX cohort treated with routine C5 inhibitors. The study used benchmarking and comparative effectiveness to evaluate the haematological response in APPOINT‐PNH if patients had received C5 inhibitors. Treatment effect was estimated using propensity scores to model the probability of trial inclusion based on baseline covariates, followed by fitting an outcome model to the APPEX cohort. Results The analysis of 125 patients showed all estimated treatment effects (95% confidence interval) favoured iptacopan over C5 inhibitors: differences in the proportion of patients achieving haemoglobin increase from baseline of ≥ 2 g/dL, 68.2% (40.9–95.6); haemoglobin levels of ≥ 12 g/dL, 53.4% (31.4–75.3); transfusion independence, 38.8% (15.1–62.5); ratio of percent change from baseline in lactate dehydrogenase levels, 0.51 (0.40–0.67); change from baseline in reticulocytes, −75.5 × 109/L (−106.9, −44.2). Conclusions Results indicate C5 inhibitor‐naive patients with PNH may experience greater haematological response with iptacopan than with C5 inhibitors. Trial Registration ClinicalTrials.gov identifier: NCT05842486

Introduction Ravulizumab replaced eculizumab as the preferred complement inhibitor for Paroxysmal Nocturnal Haemoglobinuria (PNH) in Denmark and Finland after 2020. Data on real‐world disease activity after switching are limited. Methods We conducted a case series of 20 PNH patients who transitioned from eculizumab to ravulizumab, assessing transfusion needs and breakthrough haemolysis episodes (BTH). Results In 19 of 20 patients, transfusions and BTH were stable or reduced after switching. Particularly, patients with high transfusion or BTH burden had a marked reduction in these parameters after switching. Conclusion Overall, ravulizumab provided comparable or improved disease control, supporting its use as a long‐term treatment in PNH. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission

Paroxysmal nocturnal hemoglobinuria (PNH) results from the loss of erythrocyte surface proteins, leading to complement activation and its spectrum of effects. We explore this case of a 57‐year‐old man with post‐essential thrombocythemia (ET) myelofibrosis (MF) who developed symptomatic anemia with evidence of hemolysis on lab work. While hemolysis was localized to be intramedullary based on workup, the exact diagnosis was undetermined, leading to a prolonged course of steroid therapy to control anemia. The hemolysis was eventually attributed to PNH diagnosed on flow cytometry and the patient was treated with complement inhibitors with eventual failure of therapy. He ultimately underwent a successful hematopoietic cell transplant (HCT) with post‐transplantation flow cytometry showing complete resolution of PNH. While PNH has been identified as a progression of myelodysplastic syndromes, the mechanisms of its rare development in myeloproliferative neoplasms are poorly elucidated. Furthermore, its rarity and often vague symptoms make diagnosis and treatment a challenge. This is the second reported case of a JAK2‐negative, CALR‐positive post‐ET MF and the first reported case to be treated with HCT. This case probes for further insight into the clinical significance between MF and PNH, its impact on management, and further consideration for HCT as curative therapy in such patients who fail complement inhibitor therapy.

Complement factor 5 (C5) inhibitors for paroxysmal nocturnal hemoglobinuria (PNH) may cause iron overload due to residual intravascular hemolysis (IVH) and emergent extravascular hemolysis (EVH). In PEGASUS (phase 3; NCT03500549), adults with PNH with residual anemia (hemoglobin concentration < 10.5 g/dL) after ≥3 months of eculizumab received eculizumab and pegcetacoplan for 4 weeks and were then randomized (1:1) to eculizumab or pegcetacoplan monotherapy for 16 weeks; in the following 32-week, open-label period, patients either continued pegcetacoplan or switched from eculizumab to pegcetacoplan. This post hoc analysis reports PEGASUS transfusion-related data and iron-related biomarkers to evaluate pegcetacoplan’s effects on iron regulation. Of 80 patients randomized in PEGASUS, 27 (33.8%) had baseline iron overload (serum transferrin saturation ≥ 50%). Iron overload resolved within 52 weeks of pegcetacoplan treatment in 16 of 22 patients (72.7%) with baseline and postbaseline data; 10 experienced resolution after 20 weeks. With pegcetacoplan, transfusion numbers decreased for patients with and without iron overload, hepcidin concentrations increased, and absolute reticulocyte counts (ARCs) decreased to normal range. Mean ferritin concentrations were above normal throughout the study, regardless of iron overload status. Pegcetacoplan improves iron overload-related biomarkers, including increased hepcidin concentrations and decreased ARCs, by blocking IVH and EVH and preventing anemia.

The co-occurrence of Paroxysmal nocturnal haemoglobinuria (PNH) and pregnancy has traditionally been associated with poor feto-maternal outcomes. Eculizumab, a terminal complement inhibitor, is often used in pregnant patients, but the drug is not universally available. We therefore present the first systematic review with meta-analysis of outcomes in 190 pregnancies from 135 PNH patients, comparing those receiving eculizumab and those not. We searched PubMed for studies reporting on pregnancy outcomes in PNH. Thirty-five papers were selected for inclusion, the majority of which were case studies or small series. Eculizumab was used in 131 pregnancies. There was one maternal death reported in a woman who did not receive eculizumab. A higher rate of fetal survival was observed in pregnancies where eculizumab was used (82%) than those when it was not (69%). Miscarriage (< 24 weeks gestation) occurred twice as often in women not receiving eculizumab. Intrauterine death (≥24 weeks gestation), maternal thrombosis, bleeding (both antepartum and postpartum), and pre-eclampsia were over-represented in PNH pregnancies but did not significantly differ between treatment groups. Premature birth (< 37 weeks’ gestation) was observed in 32% of eculizumab pregnancies and 44% of non-eculizumab pregnancies. We conclude that Eculizumab appears to be safe and benefits pregnant women with PNH.